Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder characterized by extracellular deposits of A peptide in senile plaques, intraneuronal neurofibrillary tangles, synapse loss, and cognitive decline (Hansen and Terry (1997) Neurobiol. Aging, 18: S71-73). It is widely believed that the accumulation of Aβ, a small peptide with a high propensity to form oligomers and aggregates, is central to the pathogenesis of AD. Aβ derives from the proteolytic cleavage of the transmembrane protein, APP (Koo (2002) Traffic 3(11): 763-770). Although a considerable amount is known about interacting proteins and processing events for APP, the physiological role(s) of APP and its related family members, APLP1 and APLP2 (amyloid precursor-like proteins 1 and 2), is still poorly understood (Koo (2002) Traffic 3(11): 763-770; Williamson et al. (1996) J. Biol. Chem., 271: 31215-31221). APP has been proposed to function in cell adhesion and motility, as well as synaptic transmission and plasticity (for a review, see Turner et al. (2003) Prog. Neurobiol. 70: 1-32).
The cloning and characterization of APP revealed that it possesses many features reminiscent of a membrane-anchored receptor. However, to date, no clear candidate has emerged as the major ligand triggering APP-mediated signal transduction at least in part because the signal transduction mediated by APP has remained incompletely understood.